New classes of optogenetic and chemogenetic tools with a feedback control

具有反馈控制的新型光遗传学和化学遗传学工具

基本信息

批准号：
10469777
负责人：
Wenjing Wang
金额：
$ 135万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2025-08-14
项目状态：
未结题

项目摘要

New classes of optogenetic and chemogenetic tools with a feedback control Project Summary Optogenetic and chemogenetic tools have revolutionized neuroscience research. They also hold great promise for gene therapy of neurological disorders, such as epilepsy, schizophrenia and anxiety disorders. For example, among the ~ 65 million people worldwide affected by epilepsy, 30% of them are resistant to current medicine but could significantly benefit from new therapies that can quickly and effectively suppress the irregular neuronal activities during seizures. However, we currently lack tools for prolonged neuronal silencing with fast response to precisely modulate the irregular neuronal activities in neurological disorders for both neuroscience research and therapeutic development. The state-of-the-art optogenetic tools for neuromodulation provide fast temporal control via light, but they are limited by light-induced tissue heating in long-lasting neuronal silencing experiments. Existing chemogenetic tools are effective for long-term neuronal silencing, however, they are limited by their slow on/off rate due to drug administration. There is a need of new tools that will enable prolonged neuronal silencing in quick response to the irregular neuronal activities in neurological disorders. Our long-term goal is to engineer modular biological designs for controlling the activities of specific neuronal pathways with tunable temporal control and minimal invasiveness for neuroscience research and potential therapeutics. In this application, we propose to design the first closed- loop chemogenetic tool with a feedback control to suppress the irregularly-high neuronal activities, and a highly-light-sensitive optogenetic tool to achieve long-lasting silencing of neuronal activities. These new tools based on membrane-tethered temporally-gated peptide agonists for G-protein-coupled receptors are highly innovative and modular, and will open up a new frontier in designing neuromodulation tools for manipulating neuronal pathways. They will also advance the basic research on neuronal circuitry and facilitate the development of potential therapeutics for manipulating neuronal pathways in patients with neurological disorders.

具有反馈控制的新型光遗传学和化学遗传学工具项目概要光遗传学和化学遗传学工具彻底改变了神经科学研究。他们也持有伟大有望用于神经系统疾病（如癫痫、精神分裂症和焦虑症）的基因治疗。例如，全球约 6500 万人患有癫痫症，其中 30% 对癫痫有抵抗力目前的药物，但可以从能够快速有效抑制的新疗法中获益匪浅癫痫发作期间的不规则神经元活动。然而，我们目前缺乏长期神经元的工具快速反应沉默，精确调节神经系统疾病中不规则的神经元活动用于神经科学研究和治疗开发。最先进的光遗传学工具神经调节通过光提供快速的时间控制，但它们受到光诱导的组织加热的限制持久的神经元沉默实验。现有的化学遗传学工具对于长期神经元有效然而，沉默由于药物管理而受到其缓慢的开/关速率的限制。有必要新工具可以使神经元长时间沉默，以快速响应不规则的神经元活动在神经系统疾病中。我们的长期目标是设计模块化生物设计来控制具有可调时间控制和微创性的特定神经元通路的活动神经科学研究和潜在的治疗方法。在此应用中，我们建议设计第一个封闭式具有反馈控制的循环化学遗传学工具，可抑制不规则的高神经元活动，以及高光敏感光遗传学工具，可实现神经元活动的持久沉默。这些新工具基于 G 蛋白偶联受体的膜束缚时间门控肽激动剂的创新和模块化，并将开辟设计用于操纵的神经调节工具的新领域神经元通路。他们还将推进神经元回路的基础研究并促进开发操纵神经系统疾病患者神经元通路的潜在疗法失调。